Selected 17,17-difluoro unsaturated androstanes



United States Patent Claims ABSTRACT OF THE DISCLOSURE Steroids of the formula where 2 -2 represents CH=CH; CHR -CH CR =C-H where R is Cl, Br or CH CH --CHR where R, is lower alkyl or thioacetyl; or

and R is l-LH; H,OH; or =0; and steroids of the formula ll J where R, is O-lower alkyl, O-cycloalkyl or O-lower alkanoyl. These steroids are prepared by a variety of pro cedures. For example, fluorination of a 3,17-dione derivative of the above-described steroids with sulfur tetrafluoride can result in the described steroids. The steroids have pharmaceutical properties. ,1

CROSS REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of my copending application Ser. No. 444,454, filed Mar. 31, 1965.

FIELD OF THE INVENTION This invention relates to certain new fluorine-substituted, ring-unsaturated steroids of the androstane series. More particularly, it relates to 17,17-difiuoro steroids having an intracyclic double bond at the 4 or the 4 and the 6 carbon atoms of the ring. These new fluorinated steroids are characterized by unexpected and valuable biological propetries, including in particular antiandrogenie activity.

SUMMARY AND DETAILS OF THE INVENTION The new compounds of this invention are 17,17-difluoro steroids represented by one of the formulas:

Qli

where R represents (H, -H), (H, -'OH) or (=OH) and the symbol Z -Z represents the C-6 to C-7 grouping of the molecule selected from where R is Cl, Br or CH and :where R is as defined above, and R is (--O-lower alkyl),

(O-cycloalkyl of 5-6 carbon atoms) or (O-lower alkan0y1).

In the above definition, lower is defined as contain ing upto 6 carbon atoms. Thus, lower alkanoyl is exemplified by formyl, acetyl, propionyl, butyryl, isobutyryl, or hexanoyl; lower alkyl is exemplified by methyl, ethyl, propyl, isopropyl, butyl or n-hexyl; and the cycloalkyl term represents cyclopentyl or cyclohgxyl.

The products of this invention can be prepared by the various methods briefly described below and more fully illustrated in the examples which follow.

The compounds of Formula 1 can be prepared in various ways. Some of them, e g., 17,17-difluoro-4,6-androstadiene-S-one or 17,17-difluoro-6u-methyl-4-androstene- 3-one, may be prepared by fluorination with sulfur tetrafluoride of the corresponding 3,17-diones. In this reaction, the C-17 0x0 group is replaced by two fluorine atoms but the conjugated 3-keto group, which is much less reactive, remains substantally unaffected under mild operating conditions, as does also the ll-keto group, if present. Compounds of Formula 1 having C-6 to C-7 unsaturation can also be prepared by oxidation with chloranil of the corresponding 17,17 difiuoro 4 androstene-3-one or -3,l1-dione, whereby a double bond is formed at C-6.

The resulting 4,6-androstadienes in turn lead to the 7a- Hi If) Diagram A Chloranll I OHaC OSH Ii] mi or y-SCOCH:

Ii a 00;

L) H O The 17,17-difluoro-4,6-androstadiene-3-ones of Formula 1 may also be prepared, generally in better yields, by an alternative route which consists in dehydrogenating a 4-androstene-3,l7-dione by treatment with chloranil to form a 4,6-androstadiene-3,17-dione, which is then reacted with sulfur tetrafluoride to produce a l7,17-difluoro- 4,6-androstadiene-3-one.

. 'Ihe 17,17-difluoro-6-halo-4-androstene-3 ones of Formula 1 are prepared bytreatment with an N-halosuccinimide of the compounds of Formula 2, whose preparation will be described later. Thus, the 17,17-difluoro-6- bror'no-4-androstene-3-ones are prepared by reaction of a l7,17-difluoro-3-acyloxy-3,S-androstadiene with N-bromosuccinimide [cf. J. Am. Chem. Soc. 82, 1230 (1960)]. The 17,17-difluoro-6-chloro-4-androstene-3-ones are prepared by reaction of a 3-alkoxy-17,17-ditluoro-3,5-androstadiene with N-chlorosuccinimide, the initial product being a 6 3-chloro compound, which can be isomerized in the presence of an acidic catalyst to the 6a-chloro compound. On dehydrogenation of a 17,17-difiuoro-6halo-4- androstene-3one with chloranil, a 17,17-difluoro-6-halo- 4,6-androstadiene-3-one is obtained [cf. J. Am. Chem. Soc. 81, 4107 (1959)]. Further, the 6-halo-4-androstene- 3-one can be dehydrohalogenated by known methods, e.g., by treatment with calcium carbonate in a solvent such as dimethylformamide, with formation of a 6,7 double bond. Both reactions lead to compounds of Formula 1 ghlese reactions are shown schematically in Diagram B e ow.

Diagram B HCllHOAc chloranil/ I $15 on Compounds of Formula 1 having a 6a,7a-oXido group are made by treating the corresponding 17,17-difluoro- 4,6-androstadiene-3-one with mono-perphthalic acid. The 60:,7oc-OXid0 compounds can be converted, by treatment with hydrogen chloride or hydrogen bromide in glacial acetic acid, to the corresponding 6-chloroor 6-bromo- 17,17 difiuoro 4,6 androstadiene-3-one, presumably through intermediate formation of the 6,7-halohydrin and subsequent dehydration.

In the compounds of Formula 1, the ll-keto group, if present, can be reduced to the ll-hydroxy compound, e.g., by treatment with pyrrolidine to give the intermediate 3-pyrrolidinyl-3,S-androstadiene, followed by reduction of the ll-keto group with lithium aluminum hydride and mild acid hydrolysis to reform the 3-keto-4-androstene (cf. Djerassi, Steroid Reactions, pp. 49-53).

Compounds of Formula 2 are prepared, in accordance with the known methods of converting a 3-keto-A -steroid to the enol acetate, by treating a 17,17-difiuoro-4-androstene-3-one, which may have an ll-keto group, either with isopropenyl acetate in the presence of an acidic catalyst (cf. Djerassi, Steroid Reactions, 1963, pp. 3742) or with acetyl chloride and acetic anhydride in pyridine (cf. Bull. Soc. Chim. 1957, 1289). Other 3-acyloxy-17,17- difluoro-3,S-androstadienes are prepared in the same manner, using the appropriate enol acylating agent. Compounds of Formula 2 having a 3-alkoxy group may be prepared similarly by known methods of enol etherification, e.g., by treatment with an alkyl orthoformate. Some of these reactions are shown in Diagram C below.

Diagram C 1H0 (O-Alkyl);

This invention is illustrated in greater detail in the following examples. In these examples, the melting points are reported as observed on a Kofler block and are uncorrected. The optical rotation determinations were made in chloroform (Chf.). The values given are followed by the letter c. and a number which indicates the concentration (grams of substance per 100 ml. of solvent).

EMBODIMENTS OF THE INVENTION EXAMPLE 1.--17,17-difluoro-4,6-androstadiene-3-one A solution of 17,17-difluoro-4-androstene-3-one (4.32 g.), recrystallized chloranil (3.8 g.) and redistilled tbutanol (75 ml.) was heated to reflux with stirring for 0.5 hour under nitrogen. The dark reaction mixture was concentrated under reduced pressure using a rotary evap- Chloram'l t-Butanol orator. The residue was dissolved in methylene chloride and passed down a column of commercial chromatographic adsorbent. The methylene chloride eluates were then washed with cold 1 N NaOH solution (2x100 ml.), water, saturated NaCl solution and dried over MgSO The solvent was removed under reduced pressure to leave a dark but crystalline residue which was further purified by chromatography on the same adsorbent g.). Elution with hexane-methylene chloride (1:1) and methylene chloride returned the crystalline 17,17-difluoro-4,6-androstadiene-B-one, 2.26 g. This was recrystallized from methylene chloride-hexane to yield a head crop of 810 mg., M.P. 152-155 C. and 170l72 C., [oz] +83 (c. 2.11, Chf.). The analytical sample was sublimed, MP. 169-172 C.

Analysis.-Calcd. for C H F O: C, 74.48; H, 7.90; F, 12.45. Found: C, 74.68; H, 8.03; F, 12.40.

Infrared:

A232 6.0 (C-3 conj. C=O 6.16 C=C 6.30 C=C and 8.55,. on)

Ultraviolet:

EXAMPLE 2 The product of Example 1 was prepared by the following reaction sequence:

F2 li NBS Ac0- l I C8003 (A) 3-acetoxy-l7,17-difluoro-3i,S-androstadiene (9.43 g.; prepared as described in Example 8 below) was dissolved in acetone (376 ml.) containing sodium acetate (6.9 g.) dissolved in water (47.0 ml.), and the mixture was cooled to 0 C. N-bromosuccinimide (10.0 g.) was added and immediately followed by glacial acetic acid (7.9 ml.), and the mixture was stirred for 3 hours at 0-5" C. and then poured into water. The crude 6 3-bromo-l7,l7-difluoro-4-androstene-3-one thus obtained was collected by filtration, thoroughly washed with water and air-dried, yield 9.5 g. Without further purification, this product was dehydrobrominated as described in Part B. The product can also be dehydrogenated by treatment with chloranil, as generally described in Examples 1 or 14, to give 6,8- bromo-17,17-difluoro-4,6-androstadiene-3-one.

(B) A solution of the product of Part A in pure dimethylformamide ml.) containing calcium carbonate (6.0 g.) was heated to reflux for 45 minutes under nitrogen and then filtered hot. The solid was washed well with ethyl acetate. The combined filtrate and washings were concentrated to about 90 ml. and the reaction product was precipitated by addition of water. The tan solid was collected by filtration, washed with water and air-dried, yield 6.7 g. The total crude product was taken up in hexane containing a trace of acetone and adsorbed onto a column of commercial chromatographic adsorbent (500 g.). Elution with hexane containing 10% acetone returned a crystalline solid, yield 7.5 g. This was recrystallized from acetone-hexane to give 17,17-difluoro-4,6-androsta- 7 diene-3-one, yield 6.2 g., M.P. 162-164 C. The infrared spectrum was identical to that of the product of Example 1.

EXAMPLE 3 The product of Example 1 was also prepared by a third method according to the following reaction sequence:

De d

(A) A solution of 4-androstene-3,17-dione (4.32 g.), recrystallized chloranil (3.8 g.), and redistilled t-butanol (75 ml.) was heated to reflux under nitrogen for 0.5 hour, and then concentrated under reduced pressure to give a green syrup. This was dissolved in acetone-hexane and allowed to stand overnight at room temperature, which resulted in the formation of large crystals mixed with some oil. These were dissolved in ethyl acetate, the solu tion washed with 5% NaOH solution, water and saturated salt solution, and then dried over MgSO Evaporation of the solvent under reduced pressure left a solid residue (2.33 g.), whose infrared spectrum showed it was 4,6- androstadiene-3,17-dione. This was further purified by chromatography followed by crystallization from acetonehexane, yield 1.5 g. (1st crop), M.P. 165.5168 C.

Infrared:

Chlorauil 6.05 (conj. C-3 C=O), 6.22 (A C=O), 6.22 (A C=C), and 6.35 (A C=C).

(B) A solution of 4,6-androstadiene-3,17-dione (7.5 g.) in methylene chloride (100 ml.) containing suspended water (1.5 ml.) was shaken with sulfur tetrafluoride (150 g.) at 20i-2 C. for 30 hours. The reaction vessel was vented, swept out with a stream of nitrogen, and the contents transferred to a separatory funnel. The methylene chloride solution was washed with water, 5% sodium bicarbonate solution, water and saturated salt solution. After drying over magnesium sulfate, the solution was evaporated to dryness under reduced pressure to afford a dark syrup showing in the infrared:

6.12 (A C=C), 6.25 (A C",C) and 8.55 1. (CF The C-17 C==O adsorption band at 5.7 8a had essentially dis- 6 8 EXAMPLE.17,17-difiuoro-7u-methyl-4- androstene-3-one (\I F2 I F2 llj/ C aCgBr l CuCl I To a stirred solution of 17,17-difluoro-4,6-androstadiene-3-one (4.10 g.) and dry tetrahydrofuran (75ml) containing cuprous chloride (150 mg.) cooled in an ice bath and under nitrogen, there was added over five minutes a solution of commercial 3M methyl magnesium bromide (13 ml.) containing suspended cuprous chloride (150 mg.) and dry tetrahydrofuran (75 ml.). The resultant mixture was stirred an additional 5 minutes after which it was poured into a slurry of ice containing concentrated hydrochloric acid (30 ml.). The product was isolated by thoroughly extracting with methylene chloride. The extracts were washed with water, 5% NaHCO solution, water and saturated salt solution. After drying over MgSO the solution was concentrated under reduced pressure to give a yellow gum. The infrared spectrum indicated that the dienone had been converted to the desired enone. The total crude product was extracted with boiling hexane, and the cooled hexane extracts placed on a column of neutral alumina (200 g., activity III). Elution with hexane returned a little gum. Further elution with hexane-benzene (1:1) returned a yellow oil which solidified when triturated with methanol. The crystalline cuts were combined and recrystallized twice from methanol to give 17,l7-difluoro-7a-methyl-4-androstene-3one as colorless plates (768 mg., 1st crop), M.P. 176.5-178 C. The mother liquors yielded an additional 255 mg. of product. The analytical sample was sublimed, [a] (c. 2.43, Chf.).

Analysis.-Calcd. for C H F O: C, 74.50; H, 8.75; F, 11.75. Found: C, 74.49; H, 8.65; F, 11.63.

Ultraviolet:

AELOH max.

The same procedure can be applied to other magnesium alkyl halides, preferably bromides or iodides, to give other 7a-alkyl steroids of the same structure, for example, the 17,17-difluoro-4-androstene-3-ones having an ethyl, propyl, isopropyl, butyl or n-hexyl group on the 7-carbon atom.

EXAMPLE 5.-17,17-difiuoro-7a-tl1ioacetyl 4-androstene-3-one 9 AnaIysis.-Calcd. for C H F O C, 66.00; H, 7.38; F, 9.92; S, 8.37. Found: C, 66.10; H, 7.47; F, 10.31; S, 8.98.

Infrared Ultraviolet:

A 237 (e=20,000) and 307 m (5 567) mux.

Starting with 17,17-difiuoro-4,6-androstadiene-3,11- dione (the product of Example 6 below), 17,17-difluoro- 7a-thioacetyl-4-androstene-3,1l-dione is obtained in the same manner, and 17,17-difluoro-1l 3-hydroxy-7a-thioacetyl-4-androstene-3-one is also obtained similarly, starting with 17,17-difluoro-11B-hydroxy-4,6-androstadiene-3- one (see Example 6 below).

EXAMPLE 6.--l7,17-difluoro-4,6-androstadiene- 3,1 l-dione This compound was prepared from 3-acetoxy-17,17-difiuoro-3,S-androstadiene-ll-one (the product of Example 10 below) by the following reaction sequence:

(A) 3 acetoxy 17,17 difluoro 3,5 androstadienell-one (3.25 g.) was converted to 6,8-bromo-17,17-difluoro-4-androstene-3,1l-dione by treatment with N-bromosuccinimide, using the procedure described in Example 2-A.

(B) The product obtained in Part A, without further purification, was dehydrobromoinated by treatment with calcium carbonate in dimethylformamide as described in Example 2-B, and isolated by the same chromatographic procedure. The crystalline chromatography fractions were combined and recrystallized from hexane-acetone to give pure 17,17-difluoro-4,6-androstadiene-3,1l-dione (1.63 g., 1st crop), M.P. 156 157" C. [a] +306 (c. 2.14, Chf.).

Analysis.--Calcd. for C H F O C, 71.30; H, 6.91; F, 11.85. Found: C, 71.59; H, 7.11; F, 11.62.

Infrared A231? 5.85 011 0:0 5.99 0-3 0:0 6.20 0:0 5.82 (0:0), and 8.58,. on)

Ultraviolet:

A323? 278 m (e=24,500)

The 6-bromo-17,17-difluorfo-4-androstene-3,1l-dione of this example can be converted to 6-bromo-17',17-difluoro- 11fl-hydroxy-4-androstene-3-one by the lithium aluminum hydride reduction method discussed earlier. The later can then be dehydrohalogenated as described above to give 17,17 difiuoro 11,8 hydroxy 4,6 androstadiene 3- one.

10 EXAMPLE 7.--17,17-difluoro-7u-rnethyl-4- androstene-3, 1 l-dione 17,17 difluoro 4,6 androstadiene 3,11 dione (5.85 g.) was allowed to react with methyl magnesium bromide in the presence of cuprous chloride, using the procedure described in Example 4. The crude product was purified by chromatography on neutral alumina (activity III) and recrystallization from acetone-hexane to give 17,17 difluoro 7 a methyl 4 androstene 3,11 dione (3.21 g.), M.P. 196-198.5 C., [u] +195 (c. 2.21, Chf.).

Analysis.CalCd. for C20H26F2O2: C, H, F, 11.25. Found: C, 71.49; H, 7.93; F, 11.30.

Infrared:

Nujol m 5.88 (0-11, 0:0), 6.04 (@6113. 0-8 0:0), 6.22 0:0, A4), and 8.56,. 0F,

Other 7a-alkyl steroids of the same structure, e.g., 17,17 difluoro 7a propyl 4 androstene 3,11 dione, the corresponding 7a-n-pentyl derivative and the like, can be prepared by the same method, using the appropriate alkly magnesium bromide. These compounds can be converted to the corresponding ll-hydroxy steroids by the already mentioned method of lithium aluminum hydride reduction.

EXAMPLE 8.3-acetoxy-17,17-difluoro-3,5

Ci -QO -(jl A solution of 17,17-difiuoro-4-androstene-3-one (5.0 g.), p toluenesulfonic acid (0.5 g.) and freshly distilled isopropenyl acetate ml.) was heated to reflux for 24 hours. Twice during this period a few milliliters of volatile material was allowed to distill from the reaction mixture. The reaction mixture was cooled and solid sodium bicarbonate was added with stirring. The solvents were removed under reduced pressure using a rotary evaporator. The residue was extracted with methylene chloride and the extract was washed with water followed'by saturated salt solution. After drying over MgSO the solvent was evaporated and the residual crystalline solid was recrystallized from methanol to give 3-acetoxy-17,17-difluoro-3,5-androstadiene as colorless needles, M.P. 97- 101 C., [a] (c. 1.95, Chf.).

Analysis.Calcd. for C H F O C, 72.00; H, 8.05; F, 10.82. Found: C, 71.94; H, 8.03; F, 10.28.

Isopropenyl Acetate Infrared:

A531? 5.70 and 8.25 (OAc), 6.0 and 6.10 (C=C) and 8.56 (0F,

Ultraviolet:

A532? 235 m (e=19,000)

1 1 EXAMPLE 9 The compound of Example 8 was also prepared by two other methods using acetic anhydride as the enol acetylation agent.

(A) Using acetic anhydride and acetyl chloride-A solution of 17,l7-difiuoro-4-androstene-3-one (21.6 g.), redistilled acetic anhydride (450 ml.), acetyl chloride (176 ml.) and pyridine (17.6 ml.) was heated to refiux for 2 hours after which the reaction mixtures was cooled in an ice bath. The precipitated product was collected by filtration. The mother liquors were concentrated under reduced pressure. The resultant solid mass was triturated with cold methanol, filtered and air-dried. The combined solids were recrystallized from methanol to yield 17.9 g. of 3-acetoxy-l7,l7-difluoro-3,5-androstadiene.

(B) Using acetic anyhdride and p-toluenesulfonic acid.-A solution of 17,17-difluoro-4-androstene-3-one (5.0 g.) in redistilled acetic anhydride (50 ml.) containing p-toluenesulfonic acid (0.4 g.) was stirred at 90 C. for 1 hour after which time it was poured into 1 liter of cold water. The reaction product was extracted with ether, the ether extracts washed with water and saturated sodium chloride solution, and dried over MgSO Evaporation of the ether left a tan syrup which crystallized when triturated with methanol. The total crude solid was recrystallized from methanol to give 3-acetoxy-l7, l7-difluoro-3,S-androstadiene, yield 3.13 g., M.P. l 101 C. (2nd crop, 0.2 g., with M.P. 95-97 C.).

Other 3-acyloxy steroids of the same structure, e.g., the l7,l7-difiuoro-3,S-androstadienes in which the 3-carbon atoms bears a propionyloxy, butyryloxy or n-pentanoyloxy substituent, can be prepared by the same procedure, using the appropriate carboxylic acid anhydride/ carboxylic acid chloride mixture.

Either procedure A or B above can be applied to 17, l7-difluoro-4-androstene-3,ll-dione to give the 3-acyloxy- 17,17-difiuoro-3,S-androstadiene-I l-ones.

EXAMPLE l0.-3-acetoxy-17,17-difluoro-3,5-

1 Isopropenyl 1 Acetate o: ACO

A solution of 17,l7-difluoro-4-androstene-3,1l-dione (5.0 g.) and freshly distilled isopropenyl acetate (100 ml.) containing p-toluenesulfonic acid (0.5 g.) was heated to reflux for 24 hours. Twice during this time the reflux condenser was removed and a few milliliters of solvent distilled. The reaction mixture was cooled and excess solid sodium bicarbonate added with stirring. The solvent was then evaporated on a rotary evaporator. The residue was extracted with boiling methylene chloride. The methylene chloride extracts were washed with water and saturated salt solution, dried over MgSO, and concentrated to a viscous syrup on a rotary evaporator. Trituration of the syrup with mehanol resulted in crystallization. The crude crystalline solid was recrystallized from methanol to afford 3-acetoxy-17,l7-difluoro-3,5-androstadiene-ll-one as colorless flat needles, yield 4.07 g., M.P. 159-166 C., 140 (c. 2.24, Chf.).

Analysis.Calcd. for C H F O C, 69.20; H, 7.20; F, 10.40. Found: C, 69.13; H, 7.24; F, 10.18.

Infrared:

A121? 5.75 (0A0), 5.89 (0-11 C=O), 6.03 (G=G), 6.13 (C=O), 8.20 (0A0), and 8.6211. (0E2) Ultraviolet:

The starting material in this example, 17,17-diflu0ro- 4-androstene-3,l1-dione, may be prepared as described in US. Patent 3,257,424.

3-autoxy- 17,l7-diflu0ro-1 1p hydroxy-3,5-androstadiene can be obtained in the same manner starting with 17,17-difluoro-l1fl-hydroxy-4-androstene-3-one. The latter is prepared by treatment of 17,l7-difluoro-4-androstene- 3,11-di0ne with pyrrolidine followed by lithium aluminum hydride reduction and regeneration of the 3-ket0 group.

EXAMPLE 11.--3ethoxy-17,17-difluoro- 3,5-androstadiene d mg? To a stirred solution of l7,l7-difluoro-4-androstene- 3-one (2.2 g.) and dry dioxane (11 ml.) containing p-toluenesulfonic acid (200 mg.) was added redistilled ethyl orthoformate (7.5 ml.). The resultant mixture was allowed to stir for 4.5 hours after which pyridine (5 ml.) was added. Water was added dropwise until the solution began to become cloudy. The product precipitated and was collected by filtration, washed with water and dried. The crude product was twice recrystallized from ether to give 3-ethoxy-l7,17-difluoro-3,S-androstadiene (335 mg., lst crop) as pale yellow prisms, M.P. l42-l45 C.,

[a] 89 (c. 2.21, Chf.).

Analysis.Calcd. for C H F O: C, 75.00; H, 8.98; F, 11.28. Found: C, 74.53; H, 8.59; F, 11.21.

Infrared:

6.05 o: o 6.15 0:0 and 8.55,. on

difluoro-4-androstene-3-one I EtO li a (Q j (A) To a stirred solution of 3-ethoxy-l7,l7-difiuoro- 3,5-androstadiene (5.38 g.) in acetone ml.) was added sodium acetate (3.06 g.) in water (31 ml.) and the NOS mixture was cooled to C. N-chlorosuccinimide (2.96 g.) was added in one portion, followed immediately by the addition of glacial acetic acid (3.06 ml.) The resultant mixture was stirred for 2 hours at 05 C., then poured into ice water. The colorless precipitate which formed was collected by filtration, washed well with water and air-dried. This solid was recrystallized with hexane to give 6,8-chloro 17,17-difluoro-4-androstene-3-one (2.78 g. 1st crop, 0.53 g. 2nd crop) as crystals melting at 133137 C. (capillary tube), [a] i0 (c. 2.31, Chf.).

Analysis.-Calcd. for C H ClF O: C, 66.70; H, 7.33; 01, 10.35; F, 11.10. Found: C, 66.76; H, 7.24; 01, 9.87; F, 11.11.

Infrared:

A232 5.95 (eonj. C3 0:0), 6.2 (A 0:0), and 8.55 1 (CF 2) Ultraviolet:

k 237 (e =14,500) and 332 my (e =51) 6aand 618 chloro 17,l7-difluoro-4-androstene-3,11- dione are obtained in the same manner, starting with 3- ethoxy-17,17-difluoro-3,S-androstadiene-1l-one. The 3,11- dione can be converted, through lithium aluminum hydride reduction as previously described, to the corresponding 3- keto-l lp-hydroxy compound.

(B) A slow stream of hydrogen chloride was passed into a stirred solution of 6fi-chloro-17,17-difluoro-4- androstene-3-one (2.44 g.) in glacial acetic acid (50 ml.) for 2 hours with the temperature being maintained between and C. The solution was then poured into water and the precipitate was collected by filtration, washed with water and air-dried. The solid was recrystallized from hexane-acetone to give 6a-chloro-17,17-difluoro-4-androstene-3-one (1.47 g.) as colorless needles, M.P. 162164 C. dec. (capillary tube), [a] +53 (c. 2.16, Chf.).

Infrared:

my 5.95 (@0115. 0-3 0:0), 6.19 (A4 0:0) and 8.55,. (CFz) Ultraviolet:

m 235 m (e =15,s00)

EXAMPLE 13.--3-cyclopentoxy-17,17-difluoro-3,5-

. androstadiene oi l Oyclopentanol EtO Infrared:

6.09 (0:0), 6.17 (C=C), and 8.55 1 (GF ANuiol max.

EXAMPLE 14.-6-chloro-17,17-difluoro-4,6-

androstadiene-3 -one my -93 O V (11 A solution of 6a-chloro-17,17-difiuoro-4-androstene-3- one (4.15 g.), freshly recrystallized chloranil (8.0 g.) and n-amyl acetate (110 ml.) containing glacial acetic acid (22 ml.) was heated to reflux under nitrogen for 9 hours after which the dark reaction mixture was cooled and then filtered. The solid was rinsed Well with ethyl acetate and the washings and original filtrate were combined and washed successively with Water, 5% sodium hydroxide solution (2x 100 ml.), water and saturated salt solution. After being dried over magnesium sulfate, the solution was evaporated under reduced pressure to leave a dark semisolid. The total crude product was dissolved in a small volume of hexane and adsorbed onto a column of neutral alumina (250 g., activity 3). A dark solid was eluted with hexane-benzene (3:1 and 1:1). The solid chromatographic fractions (ca. 1 g.) were combined and extracted thoroughly with boiling hexane. The hexane solution was cooled and then adsorbed onto a column of commercial chromatographic absorbent g.). Elution with hexane containing 1.5% of acetone returned a nearly colorless solid. The solid cuts were combined and recrystallized from ether to give 6-chloro-17,17-difluoro-4,6-androstadiene-3-one as very small cubes. The mother liquors yielded additional solid which, after recrystallization from methanol and sublimation, melted at 159162 C. (capillary tube).

Infrared:

A232 6.03 (conj. C=O), 6.21 and 6.30 (conj. C=C and 8.55,u (CF Ultraviolet:

Et OH max.

EXAMPLE 15.--17,17-difluoro-6u-methyl-4-androstene- A solution of 6u-methyl-4-androstene-3,17-dione (2.5 g.) in methylene chloride (40 ml.) containing suspended water (1.5 ml.) was shaken with sulfur tetrafluoride (92 g.) at :2 C. for 16 hours. The reaction mixture was worked up essentially as described in Example 3-B to give a dark product whose infrared spectrum was in agreement with the desired structure. This material was extracted with boiling hexane containing 5% of acetone and the extract was adsorbed onto a column of a magnesium silicat chromatographic adsorbent (100 g.). Elution 'with hexane (five 100-ml. portions) returned a little sulfur. Continued elution with hexane fractions containing, successively, 3%, 3.5%, and 4% of acetone returned about 1.5 g. of material which was recrystallized from hexaneacetone to yield, as the first crop, 1.105 g. of 17,17-difiuoro-6wmethyl-4-androstene-3-one, MJP. 157157.5 C. [a] +8O (c. 2.07, Chf.). The analytical sample was sublimed.

Analylsis.Calcd. for C H F O: C, 74.50; H, 8.75; F, 11.80. Found: C, 75.00; H, 8.89; F, 11.55.

Ultraviolet:

A 238 (e=14,700) and 288 m (e =l85) The starting material in this example, 6a-methyl-4 androstene-3,17-dione, may be prepared as described by Ringold et al. in J. Org. Chem. 22, 99 (1957).

The same procedure, when applied to 6u-methyl-4- androstene-3,11,17-trione (which may be prepared as described in US. Patent 2,842,572)) leads to 17,17-difluoro- 6a-methyl-4-androstene-3,1l-dione. Chloranil oxidation of this compound by the procedure of Examples 1 or 14 leads to l7,l7-difluoro-6-methyl-4,6-androstadiene-3,11 dione, and chloranil oxidation of 17,l7-difluoro-6a-methyl 4- androstene-S-one leads to 17,17-difluoro-6'methyl 4,6- androstadiene-3-one.

Both 17,17-difluoro-6a-methyl-4-androstene-3,11 dione and 17,17-difluoro-6-methyl-4,6-androstadiene-3,11 dione can be converted through the lithium aluminum hydride sequence to 17,17-difluoro-11p-hydroxy-6a methyl 4- androstene-3-one and 17,17-difluoro-11B hydroxy 6- methyl-4,6-androstadiene-3-one, respectively.

EXAMPLE 16.17,17-difluoro-6a,7a-oxido-4- rated sodium carbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate, and evaporated to a small volume on the steam bath. The solid which had precipitated was collected, washed with cold hexane containing a little ether and air-dried. There was thus obtained 6.4 g. of 17,17-difluoro-6a,7a-oxido-4-androstene-B-one, showing in the infrared A232 at 5.90, 6.14, 8.6 and 11.45;

Recrystallization from acetone-hexane afforded this prodnot as colorless cubes (first crop, 3.34 g.; second crop, 1.16 g.; third crop, 0.495 g.). The first crop melted at 252- 254 C. A portion of the first crop was recrystallized from acetone-hexane to give crystals melting at 253-255 C., [a] +52 (c. 1.95, Chf.), showing in the ultraviolet A 238 mu mix.

The infrared spectra of the first and third crops were identical.

Analysis.-Calcd. for C H F O C, 7.50; F, 11.75. Found: C, 70.55; H, 7.59; F, 11.78.

17 17 -difluoro-6a,7 a-oxido-4-androstene-3 ,1 l-dione and 17,17-difiuoro-11fi-hydroxy-Gu,7m-oxido-4-androstene 3- one can be obtained in the same manner, starting with 17, 17-difluoro-4,6-androstadiene-3-1l-one, respectively.

EXAMPLE 17.6-chloro-17,l7-difluoro-4,6-

androstadiene-3 -one A stirred suspension of 17,17-difluoro-6a,7a-oxido4- androstene-3-one (4.63 g.) in glacial acetic acid (60 ml.) was saturated with a slow stream of hydrogen chloride for 3 hours with the temperature being maintained at 20-25 C. During this time the suspended solid dissolved to give a clear solution, followed by precipitation of a white solid which, in turn, redissolved to give at the end of the three hours a clear tan solution which was kept at room temperature for 12 hours. The product was precipitated with ice water to yield 4.46 g. of 6-chloro-17,17-difluoro-4,6-androstadiene-3-one, M.P. 174-177 C., showing in the infrared max.

A512? 284 mp (e=20,800)

Analysis.Calcd. for C H C1F 'O: C, 67.20; H, 6.79; Cl, 10.42; F, 11.15. Found: C, 67.36; H, 6.76; Cl, 10.62; F, 11.19.

The new 17,17-difluoro steroids of this invention have all shown anti-androgenic activity, as demonstrated by tests on male rats, with some being more effective than others in this respect. Anti-androgenic activity is shown by the fact that these compounds are able to inhibit the hormonal acion of simultaneously administered testosterone propionate in castrate male rats, and to inhibit endogenous androgen (mainly testosterone) in intact male rats. Furthermore, the tests indicate that these compounds block the androgenic (virilizing) action of testosterone without blocking the anabolic (myotrophic) action, and in fact exhibit a slight anabolic effect. The degree of androgeninhibition is determined by measuring the ability of the compound to block the testosterone propionate or testosterone-induced hypertrophy of the ventral prostate, seminal vesicle in the castrate male rat and to inhibit the normal growth of these glands in the immature intact male rat. The degree of anabolic effect is estimated on the basis of the gain in weight of the body and levator ani muscle.

As is known, anti-androgenic steroids are valuable agents in the therapeutic treatment of prostatic carcinoma in male mammals [see, for example, the article by Huggins in Cancer Research 16, 825 (1956)] and have been proposed in the treatment of other disorders such as post-puberal and idiopathic hirsutism in female mammals, and the Stein-Leventhal syndrome [see, for example, Sanders et al., Steroids 3, 687 (1964), listing leading references].

It was quite unexpected to find that the compounds of this invention possess anti-androgenic activity since certain previously known 17,17-difluoro steroids are reported to be androgenic, i.e., to possess the opposite activity (see, for example, U.S. Patent 3,163,661).

Some of the compounds of this invention, in particular those having an alkyl or thioacetyl substituent at the 7- position, also possess the advantageous property of being anti-gonadotrophic, i.e., of inhibiting pituitary secretions. This property indicates usefulness in the treatment of disorders, apparently connected with excessive gonadotrophin secretion, which often occur during menopause.

Additionally, some of the compounds of this invention, in particular those having alkyl or halogen at C-6 or alkyl at C-7, have shown anti-fertility properties in test animals. For example, 6a-chloro 17,17 difluoro-4- androstene 3 one, 17,17 difluoro 6a methyl 4- androstene 3 one and 17,17 difluoro-7a-methyl-4- androstene-3-one effectively prevent implantation in female rats.

The foregoing detailed description has been given for clearness of understanding only and no unnecessary limitations are to be understood therefrom. The invention is not limited to the exact details shown and described, for obvious modifications will occur to those skilled in the art.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. The steroids represented by the formula wherein R is a group selected from the class consisting of (H, H), (H, OH) and (:0) and R is a group selected from the class consisting of (O-lower alkyl), (O-cycloalkyl of 56 carbon atoms) and (O-lower alkanoyl).

2. The steroid having the formula 3. The steroid having the formula I @5 .QU

4. The steroid having the formula 5. The steroid having the formula i C CHa U.S. Cl. X.R.

mg? UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent NOMFLA'E ,216 Dated September 30, 1969 Inventor(s) George A, Boswell It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2, line 16, change "(=0H)" to read (=0) Column 12, line 4, change "5-autoxyto read B-acetoxy- SIG ii ED AND SEALED FEB 241910 munmm. AM 2- sum, .m. Attoafi g Officer flnta 

